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The mitochondrial disulphide relay substrate FAM136A safeguards IMS proteostasis and cellular fitness

Christine Zarges1, Hanna Fieler2, Robin Alexander Rothemann1

  • 1Redox Metabolism, Institute for Biochemistry, University of Cologne, 50674, Cologne, Germany.

Redox Biology
|October 18, 2025
PubMed

Insights

Researchers identified FAM136A as a new mitochondrial protein. Its import and folding depend on the MIA40 machinery, and FAM136A is crucial for cellular proliferation and proteostasis.

Area of Science:

  • Mitochondrial biology
  • Cellular proteostasis
  • Protein import and folding

Background:

  • The mitochondrial intermembrane space (IMS) utilizes a disulphide relay system for protein import and oxidative folding.
  • Many IMS proteins with unknown functions remain to be characterized.

Purpose of the Study:

  • To identify novel substrates of the mitochondrial disulphide relay.
  • To elucidate the function of FAM136A within the IMS proteostasis network.

Main Methods:

  • Investigated FAM136A interaction with MIA40 using biochemical assays.
  • Analyzed the role of cysteines in FAM136A import and folding.
  • Assessed the impact of FAM136A deletion on cellular proliferation and stress response.
  • Examined the steady-state levels of FAM136A in relation to MIA40 and AIFM1.

Main Results:

  • FAM136A is a novel substrate of the mitochondrial disulphide relay, interacting with MIA40.
  • MIA40 introduces four disulphide bonds into FAM136A via twin-CX3C motifs, essential for its IMS import.
  • FAM136A import and steady-state levels are dependent on MIA40 and AIFM1.
  • FAM136A forms non-covalent homodimers as a mature protein.
  • FAM136A deletion impairs cellular proliferation and induces the integrated stress response, affecting other IMS proteins like HAX1 and CLPB.

Conclusions:

  • FAM136A is a critical component of the mitochondrial intermembrane space proteostasis network.
  • FAM136A's function is intrinsically linked to the MIA40-mediated disulphide relay system.
  • Dysregulation of FAM136A has significant implications for cellular health and proliferation.
Keywords:
FAM136AIntegrated stress responseMIA40Oxidative protein folding

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